Causes and Factors Associated with Neonatal Seizure and its Short-term Outcome: A Retrospective Prognostic Cohort Study

Objective: Neonatal seizures are common, difficult to diagnose and treat, and associated with a great mortality rate and long-term risk of neurodevelopmental impairments. We aimed to determine the etiology, clinical presentation, and neurodevelopmental outcome of neonatal seizures. Materials and Methods: In this cross-sectional study, 88 neonates, aged < 28 days, admitted to Mofid Children’s Hospital, Tehran, Iran, from September 2011 to 2013 with the initial diagnosis of seizure were enrolled by convenient sampling method. Data, including age, gestational age, birth weight, Apgar of the fifth minute, neonatal intensive care unit (NICU) admission, family history, type, cause, and age of seizure, EEG and paraclinic findings, anticonvulsant used for treatment, neurodevelopmental status, and the final outcome, were collected from medical records and the missed cases were completed by phone calls. The frequency and association of variables were analyzed using SPSS software. Results: Among neonates with seizures, 67% were male, 79.5% were born term, and 72.7% had normal birth weight. The most common type of seizure was multifocal clonic seizures (45.5%). The main diagnosis in neonates with seizures was hypoxic-ischemic encephalopathy (HIE) (23.9%) and hypoglycemia (10.22%). The mortality rate was 11.36% during a mean follow-up period of 21.4±6.4 months. Neurodevelopmental assessments showed that 64% were normal, 27% had global delay, and 9% had motor delay. Positive family history of epilepsy (P=0.006), low Apgar score (P=0.002) and epilepsy (P<0.001) were significantly associated with adverse neurodevelopmental outcome. Conclusion: Since HIE and hypoglycemia were the most common cause of neonatal seizures, efforts should be made to improve care during delivery and early breastfeeding.

Diagnosis is nevertheless not an easy issue, as the most efficient diagnostic tools, such as video-EEG, are not easily performable (5), and available diagnostic tools, such as computed tomography (CT) and magnetic resonance imaging (MRI) have insufficient accuracy for diagnosis of all lesions (13). In addition, although EEG is the most commonly used diagnostic tool, the accuracy of results are observer-based and various systems have been suggested to increase its performance (14,15); thus, studies have suggested a higher accuracy in using a combination of methods (13).
Initial therapy by common medications seems to be ineffective (16), and the rate of neurodevelopmental disorders and mortality are high.
Assessing the combination of etiological factors, clinical presentation, different diagnostic tools, and treatments, as well as neurodevelopmental outcome can broad the physicians' view towards neonatal seizure. Therefore, we aimed to investigate the clinical, paraclinical, and demographic details of neonatal seizure and the association with adverse neurological outcome in a referral pediatric center in Iran.

Study design
In this descriptive cross-sectional retro and prospective study, neonates referred to Mofid  (3,4), although studies in other countries have reported higher mortality rates (about 17%) (5, 6) and another study found no difference in mortality rate between neonates with seizure and neonates admitted to NICU without seizure (7). Thus, it seems necessary to dig out the reasons underlying the neonatal seizure and factors associated with its mortality.
Several risk factors for its occurrence, including preterm birth, maternal diabetes, and fetal distress, associated with the most common causes of neonatal seizure, including hypoxic-ischemic brain injury and hypoglycemia have been reported (8). Other risk factors for neonatal seizure include maternal hypothyroidism diagnosed after birth (9), and 5-min Apgar scores (10). Genetic factors also play a role in its incidence, as studies have identified the responsible mutations in familial neonatal seizures (11). Besides, abnormal electroencephalography (EEG), and cranial ultrasonography findings and presence of underlying diseases, such as congenital heart disease, have been associated with unfavorable neurodevelopmental outcome (12). the pathologist.

Statistical analysis
Descriptive analysis was used for presenting the results, including mean ± standard deviation (SD) for quantitative variables and frequency

Results
Among neonates with seizures, 66% were male.
Positive family history of epilepsy, low Apgar    score and epilepsy were significantly associated with adverse neurodevelopmental outcome, but the rest of variables were not (Table 1).

Discussion
The results of the present study indicated a mortality rate of 11.36% during a mean follow-up period of 21 (6) and an Iranian study in a rural area (7), both reporting a frequency of nearly 8%, and much lower than the study by Sabzehei and colleagues (24.4%) (3), while the percentage of unknown causes was higher in the present study than previous studies (3,4,6), which might be due to the high rate of neonates being discharged by parents (10.2%), and unwillingness to undergo LP (33%), and imaging (15.9%).
Early-onset seizure was identified as the most common time of occurrence in the present study, which is consistent with the results of previous studies (3,20). Moreover, male-dominancy of neonates with seizure in the present have been reported in some previous studies (3,6,7,17) that suggests more accurate investigations in male neonates, suspected of seizure.
The most common type of seizure in the results of the present study was multifocal clonic seizures (45.5%), which is similar to the results of the study by Gebremariam and colleagues, while some studies have reported subtle seizure as the most common type and clonic seizures as the second or third most common type of seizure (3,4,6), which might be due to the demographic and epidemiological differences in different studies or the accuracy of different diagnostic tools used.
As the type of seizure is associated with longterm neurologic outcome (21) seizure. In addition, the retrospective nature of the study, beside the fact that data was collected from one center limited the generalizability of data.
In conclusion, the results of the present study indicated HIE and hypoglycemia as the most common causes of neonatal seizures, representing the necessity to take measures to improve care during delivery and early breast-feeding. In addition, the significant association of positive family history and 5-minute Apgar score with neurodevelopmental delay in long-term follow-up demands paying more attention to the maternal/ neonatal care during delivery and precise history taking.